Evaluating a 4-marker signature of aggressive prostate cancer using time-dependent AUC.

TitleEvaluating a 4-marker signature of aggressive prostate cancer using time-dependent AUC.
Publication TypeJournal Article
Year of Publication2015
AuthorsGerke TA, Martin NE, Ding Z, Nuttall EJ, Stack EC, Giovannucci E, Lis RT, Stampfer MJ, Kantoff PW, Parmigiani G, Loda M, Mucci LA
JournalProstate
Volume75
Issue16
Pagination1926-33
Date Published2015 Dec
ISSN1097-0045
KeywordsAged, Aged, 80 and over, Area Under Curve, Biomarkers, Tumor, Cyclin D1, Disease Progression, Follow-Up Studies, Gene Expression Profiling, Humans, Male, Middle Aged, Neoplasm Invasiveness, Osteopontin, Prognosis, Prostate, Prostatic Neoplasms, PTEN Phosphohydrolase, Smad4 Protein
Abstract

BACKGROUND: We previously identified a protein tumor signature of PTEN, SMAD4, SPP1, and CCND1 that, together with clinical features, was associated with lethal outcomes among prostate cancer patients. In the current study, we sought to validate the molecular model using time-dependent measures of AUC and predictive values for discriminating lethal from non-lethal prostate cancer.

METHODS: Using data from the initial study, we fit survival models for men with prostate cancer who were participants in the Physicians' Health Study (PHS; n = 276). Based on these models, we generated prognostic risk scores in an independent population, the Health Professionals Follow-up Study (HPFS; n = 347) to evaluate external validity. In each cohort, men were followed prospectively from cancer diagnosis through 2011 for development of distant metastasis or cancer mortality. We measured protein tumor expression of PTEN, SMAD4, SPP1, and CCND1 on tissue microarrays.

RESULTS: During a median of 11.9 and 14.3 years follow-up in the PHS and HPFS cohorts, 24 and 32 men (9%) developed lethal disease. When used as a prognostic factor in a new population, addition of the four markers to clinical variables did not improve discriminatory accuracy through 15 years of follow-up.

CONCLUSIONS: Although the four markers have been identified as key biological mediators in metastatic progression, they do not provide independent, long-term prognostic information beyond clinical factors when measured at diagnosis. This finding may underscore the broad heterogeneity in aggressive prostate tumors and highlight the challenges that may result from overfitting in discovery-based research.

DOI10.1002/pros.23090
Alternate JournalProstate
PubMed ID26469352
PubMed Central IDPMC4831584
Grant ListP50 CA090381 / CA / NCI NIH HHS / United States
UM1CA16755201 / CA / NCI NIH HHS / United States
R01CA133891 / CA / NCI NIH HHS / United States
R01CA141298 / CA / NCI NIH HHS / United States
P50CA090381 / CA / NCI NIH HHS / United States
R01CA136578 / CA / NCI NIH HHS / United States
R01 CA133891 / CA / NCI NIH HHS / United States
T32 CA009001 / CA / NCI NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
R01 CA136578 / CA / NCI NIH HHS / United States
R01 CA141298 / CA / NCI NIH HHS / United States
Related Faculty: 
Massimo Loda, M.D.

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